Parathyroid hormone (PTH) is a polypeptide hormone consisting of 84-amino acid residues secreted from the parathyroid, and has a function in maintaining homeostasis of calcium concentration in the blood.
Increases in PTH concentration in the blood increase calcium concentration in the blood via an action of enhancing calcium elution from bone to blood, an action of enhancing calcium resorption at the renal tubule, or the like. PTH concentration in the blood and calcium concentration in the blood have a close relationship, and decreases in the calcium concentration in the blood enhance secretion of PTH from the parathyroid, while increases in the calcium concentration in the blood suppress secretion of PTH from the parathyroid. From such feedback system, the calcium concentration in the blood is strictly controlled within a certain range. It is considered that the calcium sensing receptor (CaSR) existing on the cell membrane of the parathyroid is the one that mainly senses changes in calcium concentration in the blood.
CaSR is one of the seven-transmembrane G protein-coupled receptors. It is known that when CaSR of the parathyroid cells is activated by extracellular calcium, it increases the calcium concentration in the cell and decreases the secretion of PTH.
It is known that secondary hyperparathyroidism is often seen in renal failure patients, and PTH secretion is facilitated continuously as renal function decreases. It is considered that in secondary hyperparathyroidism, imbalance between the PTH concentration and the calcium concentration in the blood becomes a cause for arteriosclerosis and myocardial infarction derived from renal osteodystrophy and calcification of the cardiovascular system.
Conventional therapeutic agents for secondary hyperparathyroidism were mainly vitamin D preparations. Although administration of vitamin D preparations suppresses PTH secretion from the parathyroid, it enhances calcium absorption from the intestine, thereby limiting the dosage due to concerns about increases in calcium concentration in the blood. Therefore, administration of vitamin D preparations disadvantageously failed to exhibit a sufficient therapeutic effect.
On the other hand, CaSR activating agents (agonists) have an action mechanism in which the CaSR activating agent exerts its action on the CaSR of the parathyroid by improving the sensitivity of the receptor to calcium in the blood, thereby suppressing PTH secretion from the parathyroid, which provides decreases in the calcium concentration in the blood as a secondary action. Accordingly, it can be expected that PTH concentration in the blood is decreased without causing an increase in calcium concentration in the blood. Therefore, an agent which has a CaSR activating (agonist) action is expected as a therapeutic agent for hyperparathyroidism, renal osteodystrophy, hypercalcemia or the like.
In recent years, cinacalcet which was developed as a CaSR activating agent (agonist) (for example, refer to Patent Document 1) has been used as a novel therapeutic agent for hyperparathyroidism in the clinical field. However, since cinacalcet is disadvantageous in terms of its effectiveness and safety, creation of a CaSR activating agent (agonist) with high potency and high safety is desired (refer to non-Patent Document 1, Patent Document 1 and Patent Document 2). Further, while an arylalkylamine compound having CaSR activating (agonist) action is disclosed (Patent Document 3), it differs from the compound of the present invention in its structure.